Adeno-Associated Virus Toxicity in Duchenne Muscular Dystrophy: Mechanisms and Clinical Considerations

TL;DR

This paper reviews the toxic effects of adeno-associated virus (AAV) gene therapy in Duchenne muscular dystrophy and discusses strategies to improve safety while maintaining therapeutic benefits.

Contribution

The paper provides a comprehensive review of AAV toxicity mechanisms and clinical strategies to enhance safety in DMD gene therapy.

Findings

AAV toxicity includes immune activation, vector–host interactions, and transgene overexpression.

High-dose AAV therapy can lead to severe adverse events, including multi-organ failure.

Strategies like vector redesign and immune modulation are being explored to improve safety.

Abstract

Background/Objectives: Recombinant adeno-associated virus (AAV) vectors have revolutionized gene therapy for monogenic diseases such as Duchenne muscular dystrophy (DMD). However, high systemic doses required for muscle transduction cause a spectrum of toxicities ranging from transient hepatic inflammation to fatal multi-organ failure leading to death. These adverse events have reshaped the risk–benefit considerations for gene therapy in DMD. Methods: We conducted a narrative review describing complications associated with AAV-mediated gene therapies in the DMD field. PubMed and Clinicaltrials databases were used to search for peer-reviewed manuscripts published between 1987 and 2025. Publicly available abstracts and press releases were also used to describe AAV-mediated adverse events that have been discovered. Priority was given to large prospective cohorts, meta-analyses, and high-impact publications. Results: We outlined the mechanistic basis of AAV toxicity—spanning innate and adaptive immune activation, vector–host interactions, transgene overexpression, and host vulnerability—and discussed their therapeutic implications for DMD. We also highlighted ongoing strategies for vector re-design, immune modulation, patient selection, and regulatory adaptation, aiming to improve efficacy with safety in the next generation of muscular dystrophy gene therapies. Conclusions: Patient safety remains the number one priority in the AAV-mediated gene therapies field. Achieving long-term benefits requires continued optimization of existing vectors, implementation of strict criteria for patient selection, and regulation of immune responses, with close collaboration and transparent dialog among scientists, clinicians, and regulatory agencies, informed by both successful cases as well as tragic deaths reported in the fields of neuromuscular diseases.